Severe combined immunodeficiency is a rare, life-threatening genetic disease in which the cells of the adaptive immune system fail to develop. To date, more than 20 genes have been identified to cause SCID phenotypes from which the third most common type is the recombination-deficient SCID (RAG-SCID). SCID affects 1:35,000 infants who may often seem healthy at birth but they typically experience a wide range of serious, life-threatening infections early in life and die within the first year without effective treatment. When it is diagnosed, the first aim is to treat active infections and prevent further infections. These treatments, however, are only temporary solutions, often partly effective, and they do not treat the underlying condition. The most common recombination defects are caused by mutations in RAG1, RAG2 and Artemis genes. Currently, the standard of care is allogeneic haematopoietic stem cell transplantation (allo-SCT). In allo-SCT, the deficient immune system is corrected by replacing the patient’s bone marrow with healthy, unmodified allogeneic donor stem cells from which all immune cells can properly develop. Despite the improvements, the transplant outcome and overall survival are still unsatisfactory in more than half of the patients lacking matched family or unrelated stem cell donor. Moreover, allo-SCT is intrinsically associated with the risk of graft-versus-host disease (GvHD), an immune reaction of donor T-cells directed against the recipient’s organs and tissues. This leads to a significantly inferior outcome in terms of morbidity, hospitalisation and transplant-related mortality. As allo-SCT is still facing limitations, there is an urgent need for new therapies based on the genetic correction of autologous stem cells where the patient’s own cells are modified and transplanted back. Recomb is a research consortium developing stem cell-based gene therapy (GT) as a life-saving alternative for RAG1-SCID patients. Recomb started in 2018 and is coordinated by Leiden University Medical Center (LUMC), the Netherlands. It brings together world-renowned clinical and research professionals from 17 members who have expertise in primary immunodeficiencies, and some have recently conducted the first successful clinical trials using autologous stem cell-based GT for X-SCID and ADA-SCID in patients lacking a matched donor. These trials showed significant safety and efficacy in correcting immunodeficiency, allowing children to live normal lives. Recomb aims to perform a first-in-human clinical study and provide treatment for RAG1-SCID patients. We aim to correct the deficiency by delivering the therapeutic gene into the target cells using a vector. If the transduction is successful, the introduced gene is passed to all newly formed immune cells, thus restoring the immune function and curing the patient for life after a single treatment. Using the patient’s own stem cells will exclude GvHD risk and increase survival. A unique aspect of the protocol is that the patient’s cells – not the patient – will be transported to the transduction site at LUMC. After the cells are genetically modified, they will be returned to the local centres for transplantation. Thus, the therapy is expected to be more comfortable and cost-effective for patients.